Obesity and hypertension (HT) are two epidemic health problems globally. Unfortunately, these two problems are often coupled to form obesity-related HT (OHT), but due to the poor understanding about the underlying mechanism, currently there is an almost complete lack of effective interventions against OHT. Interestingly, recent research from this project has led to the discovery that the mechanism of OHT involves sympathetic upregulation arising from obesity-induced activation of proinflammatory IKK in POMC neurons localized in the hypothalamus. Having appreciated that IKK in POMC neurons represents a converging point between obesity and HT, the long-term objective of this research is to study the involved physiological, molecular and neural circuitry basis which can eventually lead to interventional strategies in treating and preventing OHT. Preliminary studies have revealed that IKK activation in POMC neurons can promote glutamate release, and importantly, IKK and glutamate signaling in POMC neurons can similarly mediate the activation of downstream presympathetic circuitry to induce HT. Conversely, inhibition of IKK or glutamate signaling in POMC neurons can similarly counteract against OHT. Hence, this project hypothesizes that IKK in POMC neurons employs glutamate signaling from these neurons to activate downstream presympathetic neurons and drive the sympathetic induction of OHT. Three Specific Aims are proposed to test this hypothesis: (1) Study the hypertensive role of IKK and glutamate in POMC neurons; (2) Study the sympathetic basis of OHT involving IKK and glutamate in POMC neurons; (3) Study the POMC neuron-related neural circuitry in relation to OHT. A combined genetic and gene delivery approaches together with relevant cardiovascular and neural analyses will be used to carry out these Aims. All key animal models, reagents and techniques have been established in the studies which generated preliminary results, making the proposal feasible. Overall, successful completion of this project will significantly clarify the brain mechanism of OHT, and enlighten the development of interventional strategies against OHT.